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James M. Ntambi - One of the best experts on this subject based on the ideXlab platform.

  • Role of Oleic Acid in the Gut-Liver Axis: From Diet to the Regulation of Its Synthesis via Stearoyl-CoA Desaturase 1 (SCD1).
    Nutrients, 2019
    Co-Authors: Elena Piccinin, James M. Ntambi, Marica Cariello, Stefania De Santis, Simon Ducheix, Carlo Sabbà, Antonio Moschetta
    Abstract:

    The consumption of an olive oil rich diet has been associated with the diminished incidence of cardiovascular disease and cancer. Several studies have attributed these beneficial effects to oleic acid (C18 n-9), the predominant fatty acid principal component of olive oil. Oleic acid is not an essential fatty acid since it can be endogenously synthesized in humans. Stearoyl-CoA desaturase 1 (SCD1) is the enzyme responsible for oleic acid production and, more generally, for the synthesis of monounsaturated fatty acids (MUFA). The saturated to monounsaturated fatty acid ratio affects the regulation of cell growth and differentiation, and alteration in this ratio has been implicated in a variety of diseases, such as liver dysfunction and intestinal inflammation. In this review, we discuss our current understanding of the impact of gene-nutrient interactions in liver and gut diseases, by taking advantage of the role of SCD1 and its product oleic acid in the modulation of different hepatic and intestinal metabolic pathways.

  • Increased hydrophilic plasma bile acids are correlated with protection from adiposity in skin-specific Stearoyl-CoA Desaturase-1 deficient mice.
    PLOS ONE, 2018
    Co-Authors: Sabrina N Dumas, James M. Ntambi
    Abstract:

    : Stearoyl-CoA desaturase 1 (SCD1) catalyzes the rate limiting step in monounsaturated fatty acid synthesis by inserting a double bond at the delta-9 position of long-chain fatty acids. SCD1 converts stearate (18:0) to oleate (18:1n9) and palmitate (16:0) to palmitoleate (16:1n7), respectively. Mice with global and skin-specific deletion (SKO) of SCD1 exhibit increased whole body energy expenditure and protection against diet-induced adiposity, hepatic steatosis, insulin sensitivity and glucose intolerance. The mechanisms that link cutaneous lipid homeostasis with whole body energy balance are presently unknown. In this study, we reveal that SKO mice demonstrate increased skin surface free cholesterol, decreased circulating total cholesterol and increased taurine-conjugated and hydrophilic bile acids. Tauro-β-muricholic acid, which is a marker of extrahepatic bile acid synthesis, is significantly elevated in SKO plasma. Bile acid signaling through the bile acid-specific receptor TGR5 is known to be protective against obesity and metabolic disease; a phenotype that is similar to SKO mice. We therefore examined TGR5 expression and its downstream mediator, DIO2, in various tissues and found that both TGR5 and DIO2 expression were significantly increased in brown adipose tissue. In sum, we suggest that skin-derived bile acids are involved in the lean and metabolically healthy phenotype of SKO mice.

  • Role of brain Stearoyl-CoA Desaturase-1 in metabolism, obesity, and glucose homeostasis (605.2)
    The FASEB Journal, 2014
    Co-Authors: Kristin R. Harrington, Maggie S. Burhans, James M. Ntambi
    Abstract:

    The high prevalence of obesity, coupled with its potential to develop into serious health issues including type II diabetes, insulin resistance and coronary artery disease, reveals it is a significant health problem. To investigate how excess adipose tissue manifests into these health issues, we have observed the effects of a disruption in Stearoyl-CoA desaturase 1 (SCD1), which is involved in the synthesis of endogenous monounsaturated fatty acids from saturated fatty acids. We have previously demonstrated that whole-body deficiency of SCD1 in mice protects from high-fat diet-induced obesity, hepatic steatosis and insulin resistance. However, the tissue-specific contribution of SCD1 to these phenotypes remains to be fully elucidated. In the current study, we investigated the role of brain SCD1 in mediating the metabolic consequences of a high-fat diet (HFD). We fed nestin-cre+;SCD1 flox/flox brain-specific SCD1 knockout (BKO) mice a HFD for 18 weeks. We observed that both male and female BKO mice weighed...

  • monounsaturated fatty acids generated via stearoyl coa desaturase 1 are endogenous inhibitors of fatty acid amide hydrolase
    Proceedings of the National Academy of Sciences of the United States of America, 2013
    Co-Authors: Resat Cinar, James M. Ntambi, Keming Xiong, Grzegorz Godlewski, Tony Jourdan, George Kunos
    Abstract:

    High-fat diet (HFD)–induced obesity and insulin resistance are associated with increased activity of the endocannabinoid/CB1 receptor (CB1R) system that promotes the hepatic expression of lipogenic genes, including Stearoyl-CoA Desaturase-1 (SCD1). Mice deficient in CB1R or SCD1 remain lean and insulin-sensitive on an HFD, suggesting a functional link between the two systems. The HFD-induced increase in the hepatic levels of the endocannabinoid anandamide [i.e., arachidonoylethanolamide (AEA)] has been attributed to reduced activity of the AEA-degrading enzyme fatty acid amide hydrolase (FAAH). Here we show that HFD-induced increased hepatic AEA levels and decreased FAAH activity are absent in SCD1−/− mice, and the monounsaturated fatty acid (MUFA) products of SCD1, palmitoleic and oleic acid, inhibit FAAH activity in vitro at low micromolar concentrations. HFD markedly increases hepatic SCD1 activity in WT mice as well as in CB1R−/− mice with transgenic reexpression of CB1R in hepatocytes, but not in global CB1R−/− mice. Treatment of HFD-fed mice with the SCD1 inhibitor A939572 prevents the diet-induced reduction of hepatic FAAH activity, normalizes hepatic AEA levels, and improves insulin sensitivity. SCD1−/− mice on an HFD remain insulin-sensitive, but develop glucose intolerance and insulin resistance in response to chronic treatment with the FAAH inhibitor URB597. An HFD rich in MUFA or feeding mice pure oleic acid fail to inhibit hepatic FAAH activity. We conclude that MUFAs generated via SCD1 activity, but not diet-derived MUFAs, function as endogenous FAAH inhibitors mediating the HFD-induced increase in hepatic AEA, which then activates hepatic CB1R to induce insulin resistance.

  • Adipose-specific deletion of Stearoyl-CoA desaturase 1 up-regulates the glucose transporter GLUT1 in adipose tissue.
    Biochemical and Biophysical Research Communications, 2010
    Co-Authors: Chang-kee Hyun, Matthew T Flowers, Maggie S. Strable, James M. Ntambi
    Abstract:

    Stearoyl-CoA desaturase 1 (SCD1) deficiency protects mice from diet-induced obesity and insulin resistance. To understand the tissue-specific role of SCD1 in energy homeostasis, we have generated mice with an adipose-specific knockout of Scd1 (AKO), and report here that SCD1 deficiency increases GLUT1 expression in adipose tissue of AKO mice, but not global SCD1 knockout (GKO) mice. In 3T3-L1 adipocytes treated with an SCD inhibitor, basal glucose uptake and the cellular expression of GLUT1 were significantly increased while GLUT4 expression remained unchanged. Consistently, adipose-specific SCD1 knockout (AKO) mice had significantly elevated GLUT1 expression, but not GLUT4, in white adipose tissue compared to Lox counterparts. Concurrently, adiponectin expression was significantly diminished, whereas TNF-α expression was elevated. In contrast, in adipose tissue of GKO mice, GLUT4 and adiponectin expression were significantly elevated with lowered TNF-α expression and little change in GLUT1 expression, suggesting a differential responsiveness of adipose tissue to global- or adipose-specific SCD1 deletion. Taken together, these results indicate that adipose-specific deletion of SCD1 induces GLUT1 up-regulation in adipose tissue, associated with decreased adiponectin and increased TNF-α production, and suggest that GLUT1 may play a critical role in controlling glucose homeostasis of adipose tissue in adipose-specific SCD1-deficient conditions.

Toshiyuki Takagi - One of the best experts on this subject based on the ideXlab platform.

Pier Lorenzo Secchiari - One of the best experts on this subject based on the ideXlab platform.

  • diacylglycerol acyltransferase 1 stearoyl coa desaturase 1 and sterol regulatory element binding protein 1 gene polymorphisms and milk fatty acid composition in italian brown cattle
    Journal of Dairy Science, 2010
    Co-Authors: Giuseppe Conte, Marcello Mele, S Chessa, B Castiglioni, Andrea Serra, G Pagnacco, Pier Lorenzo Secchiari
    Abstract:

    Abstract Several lipogenic genes have been shown to have effects on lipid metabolism: stearoyl CoA desaturase 1 ( SCD1 ) catalyzes the desaturation of several fatty acids (FA) in the cis -Δ 9 position in mammary glands of ruminant animals, diacylglycerol acyltransferase 1 ( DGAT1 ) is a key enzyme in triacylglycerol synthesis in the mammary gland, and sterol regulatory element binding protein ( SREBP-1 ) is a transcription factor that regulates expression levels of the SCD1 gene and other genes relevant to lipid and FA metabolism in adipose tissue and mammary gland. In this work, 351 Italian Brown cows were genotyped for polymorphisms in the SCD1 , SREBP-1 , and DGAT1 genes to reveal the allelic distribution in the population. Subsequently, effects on individual milk FA composition and on cis -9 unsaturated/saturated FA ratios, a proxy of mammary stearoyl CoA desaturase activity, were investigated. The genotypes of SCD1 (A293V) and DGAT1 (K232A) were determined by an approach based on the ligation detection reaction and a universal array, whereas the genotype of SREBP-1 (84-bp insertion-deletion) was revealed by PCR amplification of intron 5. The genotype analysis showed an unbalanced distribution of alleles within all genes, being the allele with higher gene frequency at 82, 84, and 98% for SCD1 , SREBP-1 , and DGAT1 , respectively. Significant associations between SCD1 and DGAT1 polymorphisms and milk FA composition were found, whereas SREBP-1 polymorphism was not associated with milk FA composition. In particular, SCD1 showed significant association with C14:1 cis -9 and C14:1 cis -9/C14:0, which is considered the best proxy of the desaturation activity in mammary gland. The DGAT1 polymorphism had the strongest association with milk FA composition, which confirmed the key role of DGAT1 in lipid metabolism of mammary gland. However, the unbalanced distribution of alleles in all polymorphisms investigated suggested that the size of population should be increased to confirm the results of the present study.

Makoto Miyazaki - One of the best experts on this subject based on the ideXlab platform.

  • Stearoyl-CoA Desaturase-1 in the Regulation of Toll-Like Receptor Signaling and Endoplasmic Reticulum Stress Signaling
    Stearoyl-CoA Desaturase Genes in Lipid Metabolism, 2013
    Co-Authors: Tabitha C. Ting, Makoto Miyazaki
    Abstract:

    Stearoyl-CoA desaturases are a family of enzymes that play a crucial role in the endogenous synthesis of monounsaturated fatty acids, also known as de novo lipogenesis. Of the four known SCD isoforms, Stearoyl-CoA desaturase 1 (SCD1) is the most predominant and most ubiquitously expressed, with the highest induction in lipogenic tissues such as liver and adipose tissue. In this chapter, we will discuss the effects of SCD1 and its substrates, saturated fatty acids, on three levels as shown in Fig. 7.4. First, we will introduce SCD1 and its role in lipid biosynthesis. Next, we will cover intermediate responses to SCD1 modulation, such as inflammation and ER stress. Finally, we will expand our discussion of SCD1 into the context of vascular diseases such as atherosclerosis and vascular calcification. The studies discussed in this chapter are significant because cardiovascular diseases are some of the leading causes of mortality worldwide. In these diseases, lipids such as fatty acids and their metabolites can accumulate and lead to cellular dysfunction and death, known as lipotoxicity. Since SCD1 plays such an important role in fatty acid formation, a deeper understanding of this pivotal enzyme may significantly contribute to further advances in the treatment of lipid-related diseases.

  • Loss of Stearoyl-CoA Desaturase-1 Attenuates Adipocyte Inflammation Effects of Adipocyte-Derived Oleate
    Arteriosclerosis Thrombosis and Vascular Biology, 2009
    Co-Authors: Makoto Miyazaki, Harini Sampath, Chad M Paton, Minghui Zhao, Matthew T Flowers, James M. Ntambi
    Abstract:

    Background and Purpose— Adipose inflammation is crucial to the pathogenesis of metabolic disorders. This study aimed at identify the effects of Stearoyl-CoA Desaturase-1 (SCD1) on the inflammatory response of a paracrine network involving adipocytes, macrophages, and endothelial cells. Methods and Results— Loss of SCD1 in both genetic (Agouti) and diet-induced obesity (high-fat diet) mouse models prevented inflammation in white adipose tissue and improved its basal insulin signaling. In SCD1-deficient mice, white adipose tissue exhibited lower inflammation, with a reduced response to lipopolysaccharide in isolated adipocytes, but not in peritoneal macrophages. Mimicking the in vivo paracrine regulation of white adipose tissue inflammation, SCD1-deficient adipocyte-conditioned medium attenuated the induction of tumor necrosis factor (TNF) α/interleukin 1β gene expression in RAW264.7 macrophages and reduced the adhesion response in endothelial cells. We further demonstrated that the adipocyte-derived oleate...

  • Stearoyl-CoA Desaturase-1 deficiency attenuates obesity and insulin resistance in leptin-resistant obese mice.
    Biochemical and Biophysical Research Communications, 2009
    Co-Authors: Makoto Miyazaki, Harini Sampath, Matthew T Flowers, Agnieszka Dobrzyn, James M. Ntambi
    Abstract:

    Abstract Obesity and adiposity greatly increase the risk for secondary conditions such as insulin resistance. Mice deficient in the enzyme Stearoyl-CoA Desaturase-1 (SCD1) are lean and protected from diet-induced obesity and insulin resistance. In order to determine the effect of SCD1 deficiency on various mouse models of obesity, we introduced a global deletion of the Scd1 gene into leptin-deficient ob/ob mice, leptin-resistant Agouti (Ay/a) mice, and high-fat diet-fed obese (DIO) mice. SCD1 deficiency lowered body weight, adiposity, hepatic lipid accumulation, and hepatic lipogenic gene expression in all three mouse models. However, glucose tolerance, insulin, and leptin sensitivity were improved by SCD1 deficiency only in Ay/a and DIO mice, but not ob/ob mice. These data uncouple the effects of SCD1 deficiency on weight loss from those on insulin sensitivity and suggest a beneficial effect of SCD1 inhibition on insulin sensitivity in obese mice that express a functional leptin gene.

  • Association of Stearoyl-CoA Desaturase 1 Activity With Familial Combined Hyperlipidemia
    Arteriosclerosis Thrombosis and Vascular Biology, 2008
    Co-Authors: Rebecca Mar-heyming, Makoto Miyazaki, Daphna Weissglas-volkov, Nicholas A. Kolaitis, Narimaan Sadaat, Christopher L. Plaisier, Päivi Pajukanta, Rita M. Cantor, Tjerk W.a. De Bruin, James M. Ntambi
    Abstract:

    Objective— Stearoyl-CoA desaturase 1 (SCD1) is the rate-limiting enzyme involved in the synthesis of monounsaturated fatty acids, and in mice SCD1 activity is associated with plasma triglyceride levels. We used the fatty acid desaturation index (the plasma ratio of 18:1/18:0) as a marker of SCD1 activity to investigate the relationship of SCD1 to familial combined hyperlipidemia (FCHL). Methods and Results— The fatty acid desaturation index was measured in 400 individuals from 18 extended FCHL pedigrees. FCHL-affected individuals exhibited increased SCD1 activity when compared to unrelated controls ( P 2 =0.48, P =2.2×10 −11 ) in this study sample. QTL analysis in 346 sibling pairs from 18 FCHL families revealed suggestive linkage of the desaturation index to chromosomes 3p26.1 to 3p13 (z=2.7, P =0.003), containing the peroxisome proliferator-activated receptor gamma (PPARγ) gene, and 20p11.21 to 20q13.32 (z=1.7, P =0.04), containing the hepatocyte nuclear factor 4, alpha (HNF4α) gene. A specific haplotype of HNF4α was found to be associated with the desaturation index in these FCHL families ( P =0.002). Conclusion— Our results demonstrate that the fatty acid desaturation index is a highly heritable trait that is associated with the dyslipidemia observed in FCHL.

  • Metabolomics reveals that hepatic Stearoyl-CoA desaturase 1 downregulation exacerbates inflammation and acute colitis.
    Cell Metabolism, 2008
    Co-Authors: Chi Chen, Makoto Miyazaki, James M. Ntambi, Yatrik M. Shah, Keiichirou Morimura, Kristopher W. Krausz, Terrilyn A. Richardson, Edward T. Morgan, Jeffrey R. Idle, Frank J Gonzalez
    Abstract:

    To investigate the pathogenic mechanism of ulcerative colitis, a dextran sulfate sodium (DSS)-induced acute colitis model was examined by serum metabolomic analysis. Higher levels of stearoyl lysophosphatidylcholine and lower levels of oleoyl lysophosphatidylcholine in DSS-treated mice compared to controls led to the identification of DSS-elicited inhibition of Stearoyl-CoA desaturase 1 (SCD1) expression in liver. This decrease occurred prior to the symptoms of acute colitis and was well correlated with elevated expression of proinflammatory cytokines. Furthermore, Citrobacter rodentium-induced colitis and lipopolysaccharide treatment also suppressed SCD1 expression in liver. Scd1 null mice were more susceptible to DSS treatment than wild-type mice, while oleic acid feeding and in vivo SCD1 rescue with SCD1 adenovirus alleviated the DSS-induced phenotype. This study reveals that inhibition of SCD1-mediated oleic acid biogenesis exacerbates proinflammatory responses to exogenous challenges, suggesting that SCD1 and its related lipid species may serve as potential targets for intervention or treatment of inflammatory diseases.

Tsuneaki Ogata - One of the best experts on this subject based on the ideXlab platform.